Interleukin 1 beta (IL-1 beta) is a pro-inflammatory cytokine which is expressed as a precursor called pro-IL-1 beta by activated macrophages, monocytes and dendritic cells. The precursor is cleaved by caspase-1 to form the biologically active and secreted form of IL-1 beta. Binding of IL-1 beta binds to its receptor, IL-1 receptor type I (IL-1R1), allows the recruitment of a second receptor subunit, the IL-1R accessory protein (IL-1RAP). The formed complex is competent of signal transduction. Being a key mediator in the inflammatory response, the cytokine affects a number of cellular activities such as cell proliferation, differentiation, and apoptosis. Therefore, IL-1 beta is considered an important target for a variety of drugs.
Several antibodies to IL-1 beta have previously been reported. R&D Systems, Inc. produces and sells the murine anti-human IL-1 beta/IL-1F2 antibody MAB201 (R&D Systems, Inc., cat. no. MAB201), a full-length immunoglobulin IgG1, which is produced in hybridoma culture.
MAB201, which displays a half-maximum neutralizing potency range from 6.6 to 20 pM according to the supplier, has been humanized by grafting its CDRs onto human kappa chain germline sequence and gamma chain VH-2 acceptor sequences (US20030026806, AMGEN, Inc.) to yield a full-length immunoglobulin.
XOMA052, also known as AB7 or gevokizumab, is a humanized IgG2, i.e. a full-length immunoglobulin (OWYANG, A., et al. XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1 beta-mediated diseases. mAbs 2011, vol. 3, p. 49-60; EP 1899378 B, XOMA TECHNOLOGY, Ltd.). Its variable domains were humanized to match a human kappa 1 light chain and a human VH2 heavy chain. Its CDRs are identical to MAB201 with the exception of one conservative point mutation in CDR-H2.
Typically, after CDR-grafting for, e.g., humanization purposes, an antibody having accommodated new CDRs from a CDR-donor antibody experiences a drop in potency when compared to the CDR-donor antibody. It is therefore a true challenge, if successful at all, to further engineer the generated CDR-acceptor antibody such that the potency is close or equal to the CDR-donor antibody.
Moreover, for use in medical treatments it is mandatory, besides providing a good biological potency of the antibody, to generate antibodies with enhanced drug-like properties, e.g., high stability and sufficient solubility.
Hence, there is a need for novel antibodies and in particular antibody fragments, which overcome the disadvantages of the existing antibodies in the art. The invention provides such compounds, as well as methods for preparing and using these.